BAG6 prevents the aggregation of neurodegeneration-associated fragments of TDP43

Kasu, Yasar Arfat; Arva, Akshaya; Johnson, Jess; Sajan, Christin; Manzano, Jasmin; Hennes, Andrew; Haynes, Jacy; Brower, Christopher S.

doi:10.1016/j.isci.2022.104273

Cited by 12 publications

(9 citation statements)

References 83 publications

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“…We individually validated a set of additional hits from our primary screen: RNA binding proteins (Fig. 3A, yellow cluster) such as G3BP1 and PUM1, and BAG6, a cytosolic chaperone ( 33 ). We also examined the genes that stood out in our neuronal screen for increased αSyn levels, such as ARID2 .…”

Section: Resultsmentioning

confidence: 99%

Sequential CRISPR screening reveals partial NatB inhibition as a strategy to mitigate alpha-synuclein levels in human neurons

Santhosh Kumar,

Naseri,

Pather

et al. 2024

Sci. Adv.

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Alpha-synuclein (αSyn) protein levels correlate with the risk and severity of Parkinson’s disease and related neurodegenerative diseases. Lowering αSyn is being actively investigated as a therapeutic modality. Here, we systematically map the regulatory network that controls endogenous αSyn using sequential CRISPR-knockout and -interference screens in an αSyn gene ( SNCA )–tagged cell line and induced pluripotent stem cell–derived neurons (iNeurons). We uncover αSyn modifiers at multiple regulatory layers, with amino-terminal acetyltransferase B (NatB) enzymes being the most potent endogenous αSyn modifiers in both cell lines. Amino-terminal acetylation protects the cytosolic αSyn from rapid degradation by the proteasome in a Ube2w-dependent manner. Moreover, we show that pharmacological inhibition of methionyl-aminopeptidase 2, a regulator of NatB complex formation, attenuates endogenous αSyn in iNeurons carrying SNCA triplication. Together, our study reveals several gene networks that control endogenous αSyn, identifies mechanisms mediating the degradation of nonacetylated αSyn, and illustrates potential therapeutic pathways for decreasing αSyn levels in synucleinopathies.

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Section: Resultsmentioning

confidence: 99%

Sequential CRISPR screening reveals partial NatB inhibition as a strategy to mitigate alpha-synuclein levels in human neurons

Santhosh Kumar,

Naseri,

Pather

et al. 2024

Sci. Adv.

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“…For instance, Sec1 Family Domain Containing 1 ( SCFD1 ), a significant risk factor for ALS patients, exhibits overlapping gene regulatory effect with eQTL, pQTL, haQTL, and meQTL 19 . BAG Cochaperone 6 (BAG6), which senses proteolytic fragments and prevents aggregation of TDP-43 fragments, exerts regulatory effect on eQTL, meQTL, and sQTL 20 . Myelin associated oligodendrocyte basic protein (MOBP), another prominent ALS risk gene, is enriched by eQTL, haQTL, and meQTL 21 .…”

Section: Resultsmentioning

confidence: 99%

Network medicine informed multi-omics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis

Yu,

Xu,

Dutta

et al. 2024

Preprint

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Background and Objectives: Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. To date, the challenge to establishing effective treatment for ALS remains formidable, partly due to inadequate translation of existing human genetic findings into actionable ALS-specific pathobiology for subsequent therapeutic development. Methods: This study evaluates the feasibility of network medicine methodology via integrating human brain-specific multi-omics data to prioritize drug targets and repurposable treatments for ALS. Results: Using human brain-specific genome-wide quantitative trait loci (x-QTLs) under a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in various known ALS pathobiological pathways, including regulation of T cell activation, monocyte differentiation, and lymphocyte proliferation. Specifically, we leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on brain-specific expression quantitative trait loci (QTL) (eQTL), protein QTLs (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Applying network proximity analysis of predicted ALS-associated gene-coding targets and existing drug-target networks under the human protein-protein interactome (PPI) model, we identified a set of potential repurposable drugs (including Diazoxide, Gefitinib, Paliperidone, and Dimethyltryptamine) for ALS. Subsequent validation established preclinical and clinical evidence for top-prioritized repurposable drugs. Discussion: In summary, we presented a network-based multi-omics framework to identify potential drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.

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“…The involvement of GET4 in AD and neurodegeneration is limited, with few roles associated with it. However, the GET4 gene has altered poly(A) site usage as a result of WT tau [ 74 ], a protein known to make fibrils in AD, that can bind disease-causing fragments of TDP-43 219 and contribute to ALS [ 75 ]. Furthermore, GET4 and BAG6 can interact with FOBOX7, a PD-causing gene [ 76 ], suggesting that GET4 can be linked to neurodegeneration, but its role in MERCS modulation is unknown.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide CRISPR/Cas9 screen shows that loss of GET4 increases mitochondria-endoplasmic reticulum contact sites and is neuroprotective

Wilson,

Yu,

Leal

et al. 2024

Cell Death Dis

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Organelles form membrane contact sites between each other, allowing for the transfer of molecules and signals. Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) are cellular subdomains characterized by close apposition of mitochondria and ER membranes. They have been implicated in many diseases, including neurodegenerative, metabolic, and cardiac diseases. Although MERCS have been extensively studied, much remains to be explored. To uncover novel regulators of MERCS, we conducted a genome-wide, flow cytometry-based screen using an engineered MERCS reporter cell line. We found 410 genes whose downregulation promotes MERCS and 230 genes whose downregulation decreases MERCS. From these, 29 genes were selected from each population for arrayed screening and 25 were validated from the high population and 13 from the low population. GET4 and BAG6 were highlighted as the top 2 genes that upon suppression increased MERCS from both the pooled and arrayed screens, and these were subjected to further investigation. Multiple microscopy analyses confirmed that loss of GET4 or BAG6 increased MERCS. GET4 and BAG6 were also observed to interact with the known MERCS proteins, inositol 1,4,5-trisphosphate receptors (IP3R) and glucose-regulated protein 75 (GRP75). In addition, we found that loss of GET4 increased mitochondrial calcium uptake upon ER-Ca2+ release and mitochondrial respiration. Finally, we show that loss of GET4 rescues motor ability, improves lifespan and prevents neurodegeneration in a Drosophila model of Alzheimer’s disease (Aβ42Arc). Together, these results suggest that GET4 is involved in decreasing MERCS and that its loss is neuroprotective.

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BAG6 prevents the aggregation of neurodegeneration-associated fragments of TDP43

Cited by 12 publications

References 83 publications

Sequential CRISPR screening reveals partial NatB inhibition as a strategy to mitigate alpha-synuclein levels in human neurons

Sequential CRISPR screening reveals partial NatB inhibition as a strategy to mitigate alpha-synuclein levels in human neurons

Network medicine informed multi-omics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis

Genome-wide CRISPR/Cas9 screen shows that loss of GET4 increases mitochondria-endoplasmic reticulum contact sites and is neuroprotective

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